Diagnosis of neurodegenerative disorders

ABSTRACT

Methods are provided for non-invasive early screening of a subject for a neurodegenerative disorder, by analyzing one or more parameters associated with the neurodegenerative disorder.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.61/061,553 filed Jun. 13, 2008 and U.S. Provisional Application No.61/184,758, filed Jun. 5, 2009, which applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is a progressive degenerative disease of thecentral and peripheral nervous systems. The risk of developingParkinson's disease increases with age, and afflicted individuals areusually adults over 40. Parkinson's disease occurs in all parts of theworld, and affects more than one million individuals in the UnitedStates alone. There are several other conditions that have the featuresof Parkinson's disease and are referred to as Parkinson's-like diseases.Both can be characterized by tremor, hypokinesia, rigidity, and posturalinstability.

The underlying causes of Parkinson's disease and Parkinson's-likediseases are numerous, and diagnosis can be complex. Parkinson's diseaseor Parkinson's-like disease is characterized by degeneration ofdopaminergic neurons of the substantia nigra. The substantia nigra is aportion of the lower brain, or brain stem that helps control voluntarymovements. The shortage of dopamine in the brain caused by the loss ofthese neurons may cause the observable disease symptoms.

There is a need for diagnosis and/or pre-motor diagnosis of Parkinson'sdisease or Parkinson's-like disease. Such diagnosis coupled withtreatments alleviating symptoms or preventing further onset of symptomswould be beneficial. Currently there are a number of agents being testedto modify disease progression, as symptomatic treatments typically leadto unacceptable side-effects over time. Accordingly, means for screeningsubjects for Parkinson's disease or Parkinson's-like disease would beuseful in insuring that appropriate treatments are promptly provided.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method of screening asubject for Parkinson's disease or Parkinson's-like disease comprising:(a) obtaining an electrocardiogram (EKG) result from said subject; (b)comparing said EKG result to an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease; and (c)identifying said subject as suffering from or prone to Parkinson'sdisease or Parkinson's-like disease if said EKG result falls in said EKGresult range.

In some embodiments, the EKG result comprises a heart rate variability(HRV) result. In some embodiments, the HRV result comprises a timedomain measure. In some embodiments, the measure is selected from groupconsisting of standard deviation of R-R intervals (SDNN), the standarddeviation of the heart rate (SDHR), the root mean square difference ofsuccessive RR intervals (RMSSD) and the percentage number of consecutiveRR intervals differing by more than 50 msec (pNN50). In someembodiments, the HRV result comprises a geometric/non-linear measure. Insome embodiments, the measure is selected from group consisting of shortterm HRV (SD1) and long term HRV (SD2) measured from Poincaré plots, theintegral of density distribution (RR triangular index) and thetriangular interpolation of NN (TINN). In some embodiments, the HRVresult comprises a frequency domain measure. In some embodiments, themeasure is selected from group consisting of very low frequency, VLF(0-0.04 Hz), low frequency, LF (0.04-0.15 Hz) and high frequency, HF(0.15-0.4 Hz), total power and LF/HF ratio.

In some embodiments, the subject is in a wakeful state or awake whileobtaining the EKG result. In some embodiments, the EKG result isobtained for at least 1 minute, at least 2 minutes, at least 3 minutes,at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8minutes, at least 9 minutes, at least 10 minutes, at least 15 minutes,at least 20 minutes, at least 3-5 minutes, at least 5-10 minutes, or atleast 15-20 minutes. In some embodiments, the subject has been diagnosedwith a REM sleep behavioral disorder (RBD). In some embodiments, thesubject has a lower RMSSD than a subject not having an EKG resultfalling into an EKG result range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower pNN50 than a subject not having an EKG resultfalling into an EKG result range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower SDNN than a subject not having an EKG resultfalling into an EKG result range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower SD1 than a subject not having an EKG resultfalling into an EKG result range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower SD2 than a subject not having an EKG resultfalling into an EKG result range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower RR triangular index than a subject not having anEKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower TINN than a subject not having anEKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower VLF (ms²) than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower LF (ms²) than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower HF (ms²) than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower Total Power (ms²) than a subjectnot having an EKG result falling into an EKG result range predeterminedto be indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject has a lower LF(nu) than a subject nothaving an EKG result falling into an EKG result range predetermined tobe indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject has a lower HF(nu) than a subject nothaving an EKG result falling into an EKG result range predetermined tobe indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject has a lower LF/HF ratio than a subject nothaving an EKG result falling into an EKG result range predetermined tobe indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject being screened has not been previouslydiagnosed as having Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject does not exhibit any motor symptomsindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has been assessed to be 0 on the Hoehn and Yahrscale. In some embodiments, the subject has not been assessed on theHoehn and Yahr scale. In some embodiments, the subject has been assessedto be 0 on the Unified Parkinson's Disease Rating Scale (UPDRS) scale.In some embodiments, the subject has not been assessed on the UPDRSscale. In some embodiments, the subject further has a symptom selectedfrom the group consisting of constipation, olfactory dysfunction,psychological symptom, cognitive dysfunction, depression, sleepdisorder, and RBD. In some embodiments, the subject further undergoesgenetic testing for Parkinson's disease or Parkinson's-like disease oralready has been identified as carrying a parkinsonogenic gene mutation.In some embodiments, the subject further undergoes cardiac imaging. Insome embodiments, the subject undergoes Metaiodobenzylguanidine (MIBG)scintigraphy. In some embodiments, the subject further undergoes brainimaging. The brain imaging can include PET or MRI. In some embodiments,the subject is further considered for inclusion into a clinical trial.In some embodiments, the subject is prescribed a neuroprotective agentor therapy. The neuroprotective agent or therapy can be exercise,antioxidants, immunosuppressive calcineurin inhibitors, NOS inhibitors,sigma-1 modulators, AMPA antagonists, Ca2+ channel blockers, estrogenagonists, MAO-B inhibitors, kinase inhibitors, mitochondrial modulatorsor enhancers, alpha synuclein modulators, glycoprotein IIb/IIIaantagonists, erythropoietin, astaxanthin, boswellia, caffeine, curcumin,E vitamins, tocotrienols, flavonoids, naringenin, huperzine, orubiquinol.

In another aspect, the present invention provides a method of diagnosingprodromal Parkinson's disease or Parkinson's-like disease comprising (a)measuring heart rate variability (HRV) of a subject; (b) comparing theHRV result of the subject to an HRV range predetermined to be indicativeof Parkinson's disease or Parkinson's-like disease; and (c) diagnosingthe subject as suffering from or prone to prodromal Parkinson's diseaseor Parkinson's-like disease if the HRV result of the subject falls inthe HRV result range; wherein the subject has a symptom selected fromthe group consisting of REM sleep behavioral disorder (RBD), olfactorydysfunction, constipation, depression, cognitive deficits, very mildmotor deficits suggestive of a motor disease or disorder, or acombination thereof.

In some embodiments, the HRV is measured by electrocardiogram (EKG). Insome embodiments, the EKG result is obtained for at least 1 minute, atleast 2 minutes, at least 3 minutes, at least 5 minutes, at least 6minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, atleast 10 minutes, at least 15 minutes, at least 20 minutes, at least 3-5minutes, at least 5-10 minutes, or at least 15-20 minutes. In someembodiments, the HRV result comprises a time domain measure. In someembodiments, the measure is selected from group consisting of standarddeviation of R-R intervals (SDNN), the standard deviation of the heartrate (SDHR), the root mean square difference of successive RR intervals(RMSSD) and the percentage number of consecutive RR intervals differingby more than 50 msec (pNN50). In some embodiments, the HRV resultcomprises a geometric/non-linear measure. In some embodiments, themeasure is selected from group consisting of short term HRV (SD1) andlong term HRV (SD2) measured from Poincaré plots, the integral ofdensity distribution (RR triangular index) and the triangularinterpolation of NN (TINN). In some embodiments, the HRV resultcomprises a frequency domain measure. In some embodiments, the measureis selected from group consisting of very low frequency, VLF (0-0.04Hz), low frequency, LF (0.04-0.15 Hz) and high frequency, HF (0.15-0.4Hz), total power and LF/HF ratio.

In some embodiments, the subject has a lower SDNN than a subject nothaving an EKG result falling into an EKG result range predetermined tobe indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject has a lower SD1 than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower SD2 than a subject not having anEKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower RR triangular index than a subjectnot having an EKG result falling into an EKG result range predeterminedto be indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject has a lower TINN than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower VLF(ms²) than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower LF(ms²) than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower HF(ms²) than a subject not havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject has a lower Total Power (ms²) than a subjectnot having an EKG result falling into an EKG result range predeterminedto be indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject has a lower LF(nu) than a subject nothaving an EKG result falling into an EKG result range predetermined tobe indicative of Parkinson's disease or Parkinson's-like disease. Insome embodiments, the subject has a lower HF(nu) than a subject nothaving an EKG result falling into an EKG result range predetermined tobe indicative of Parkinson's disease, Parkinson's-like disease orprodromal Parkinson's disease. In some embodiments, the subject has alower LF/HF ratio than a subject not having an EKG result falling intoan EKG result range predetermined to be indicative of Parkinson'sdisease or Parkinson's-like disease. In some embodiments, the subject isin a wakeful state or awake while measuring the HRV. In someembodiments, the subject has been diagnosed with a REM sleep behavioraldisorder (RBD). In some embodiments, the subject has a lower RMSSD thana subject not having an HPV result falling into the HPV result rangepredetermined to be indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has a lowerpNN50 than a subject not having an HRV result falling into the HRVresult range predetermined to be indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has not beenpreviously diagnosed as having Parkinson's disease or Parkinson's-likedisease. In some embodiments, the subject does not exhibit any motorsymptoms indicative of Parkinson's disease or Parkinson's-like disease.In some embodiments, the subject has been assessed to be 0 on the Hoehnand Yahr scale. In some embodiments, the subject has not been assessedon the Hoehn and Yahr scale. In some embodiments, the subject has beenassessed to be 0 on the Unified Parkinson's Disease Rating Scale (UPDRS)scale. In some embodiments, the subject has not been assessed on theUPDRS scale. In some embodiments, the subject further undergoes genetictesting for Parkinson's disease or Parkinson's-like disease or hasalready been tested for a genetic risk for Parkinson's disease orParkinson's-like disease. In some embodiments, the subject furtherundergoes brain imaging. The brain imaging can be PET or MRI. In someembodiments, the subject is further considered for inclusion into aclinical trial. In some embodiments, the subject is prescribed aneuroprotective agent. In some embodiments, the neuroprotective agentsare selected from the group consisting of antioxidants,immunosuppressive calcineurin inhibitor, NOS inhibitor, sigma-1modulator, AMPA antagonist, Ca2+ channel blocker, estrogen agonist,glycoprotein IIb/IIIa antagonists, erythropoietin, astaxanthin,boswellia, caffeine, curcumin, E vitamins, tocotrienols, flavonoids,naringenin, huperzine and ubiquinol.

In another aspect, the present invention provides an algorithm forcomparing the EKG result from a subject undergoing screening forParkinson's disease or Parkinson's-like disease to an EKG result rangepredetermined to be indicative of Parkinson's disease, Parkinson's-likedisease, or prodromal Parkinson's disease or Parkinson's-like disease.In some embodiments, the algorithm is used to determine if the EKGresult from the subject falls in the EKG result range, therebydetermining whether the subject is suffering from or prone toParkinson's disease, Parkinson's-like disease, or prodromal Parkinson'sdisease or Parkinson's-like disease. In some embodiments, the algorithmis part of software.

In another aspect, the present invention provides a kit for carrying outthe method of the present invention, the kit comprising reagents andinstruments for measuring EKG of a subject undergoing screening forParkinson's disease or Parkinson's-like disease. In some embodiments,the kit further comprises software for comparing the EKG result of thesubject with an EKG result range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease. In some embodiments,the kit further comprises instructions for use of the kit. In someembodiments, the kit further comprises a neuroprotective agent. In someembodiments, the kit further comprises material for olfactory testing.In some embodiments the test might include web-based tools for measuringHRV abnormalities.

In yet another aspect, the present invention provides a method forscreening a subject for a neurodegenerative/neurological disordercomprising, obtaining data from a subject wherein said data areassociated with one or more parameter related to saidneurodegenerative/neurological disorder to produce an analysis result;comparing said analysis result to information from a control, whereinsaid information is predetermined to indicate absence of saidneurodegenerative/neurological disorder. In some embodiments, theneurodegenerative/neurological disorder is selected from the groupconsisting of ADHD, Alzheimer's disease (AD), amyotrophic lateralsclerosis (ALS; Lou Gehrig's disease), Bell's Palsy, Cerebral Palsy,chemotherapy-induced neuropathies (e.g., from vincristine, paclitaxel,bortezomib), chorea-acanthocytosis, Creutzfeldt-Jakob Disease (CJD),progressive supranuclear palsy, corticobasal degeneration,fronto-temporal dementia, dementia, diabetes-induced neuropathies,diffuse Lewy body disease, Epilepsy, Essential Tremor, Friedreich'sataxia, Guillain-Barre Syndrome, Hemifacial Spasm, Huntington's disease(HD), Movement Disorders, Multiple Sclerosis, Multisystem Atrophy (MSA),Nervous System Tumors, Neurofibromatosis, Neuropathy, ocular diseases(ocular neuritis), Parkinson's disease (PD), Periodic Limb MovementDisorder, primary lateral sclerosis, Seizure Disorders, Tourette'sSyndrome or Traumatic Brain Injury. In some embodiments, the parameteris selected from a group of parameters consisting of olfactorydysfunction, REM sleep behavioral disorder (RBD), constipation,depression, cognitive deficits, heart rate variability or a combinationthereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 depicts a scatter plot providing HRV analysis for a control andRBD subject.

FIG. 2 depicts time domain measures HRV between control subjects andpatients with RBD. The various measures are a. SDNN—standard deviationof RR intervals b RMSSD—the root mean square difference of successive RRintervals c. pNN50—percentage of the number of pairs of adjacent normalRR intervals differing by more than 50 ms. SDNN (p<0.01), RMSSD (p<0.03)and pNN50 (p<0.03) are all significantly less for the RBD patientscompared to control subjects. The horizontal lines indicate the meanvalues. Notice that for all time domain parameters, all data for RBDpatients is below the average line for the control subject.

FIG. 3 depicts frequency domain measures of HRV as calculated by FastFourier Transform (FFT) between control subjects and patients with RBD.The measures shown are: a.) VLF (ms²)—spectral power in the very lowfrequency band; b.) LF (ms²)—Low Frequency power; c.) HF (ms²)—HighFrequency power; and d.) Total power (ms²)—total power of VLF, LF and HFbands. The VLF (p<0.04), LF (p<0.01), HF (p<0.03) and total spectralpower (p<0.01) all were significantly lower in the RBD patient groupcompared to the control group.

FIG. 4 shows time domain measures of HRV between RBD patients and thecontrol group.

FIG. 5 shows geometric/non-linear measures of HRV between RBD patientsand the control group.

FIG. 6 shows frequency domain measures of HRV between RBD patients andthe control group.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, methods are provided to screen a subject for aneurological or neurodegenerative disorder (used interchangeablyherein). In one aspect, the present invention provides a method ofscreening a subject for Parkinson's disease or Parkinson's-like diseasecomprising (a) obtaining an electrocardiogram (EKG) result from thesubject; (b) comparing the EKG result to an EKG result rangepredetermined to be indicative of Parkinson's disease orParkinson's-like disease; and (c) identifying the subject as sufferingfrom or prone to Parkinson's disease or Parkinson's-like disease if theEKG result falls in the EKG result range. In another aspect, the presentinvention provides a method for screening a subject for aneurodegenerative disorder comprising, (a) obtaining data from a subjectwherein the data are associated with one or more parameter related tothe disorder to produce an analysis result; (b) comparing the analysisresult to information from a control, wherein the information ispredetermined to indicate absence of the disorder.

Neurodegenerative diseases and disorders are a condition in which cellsof the brain and/or spinal cord are lost. The brain and spinal cord arecomposed of neurons that p different functions such as controllingmovements, processing sensory information, and making decisions. Cellsof the brain and spinal cord are not readily regenerated en masse, soexcessive damage can be devastating. Neurodegenerative diseases resultfrom deterioration of neurons or their myelin sheath which over timewill lead to dysfunction and disabilities. Neurodegenerative diseasesare crudely divided into two groups according to phenotypic effects,although these are not mutually exclusive: conditions causing problemswith movements, such as ataxia, and conditions affecting memory andrelated to dementia.

Parkinson's Disease

Parkinson's disease is a neurodegenerative disease. Many of the signsand symptoms associated with Parkinson's disease can precede typicalParkinson's disease, in some cases by many years. Involvement of thedopaminergic substantia nigra, which underlies the primary motorfeatures of the disease, occurs at a time when the disease is welladvanced at a neuropathological level, an observation that may accountfor the difficulties in successfully testing new drugs for potentialdisease modifying properties only after Parkinson's disease is evident.As a result, there is increasing interest in identifying pre-motor orprodromal signs and symptoms of Parkinson's disease in order to identifythe disorder in its earliest stages, well before motor symptoms are inevidence. In one embodiment, a low-cost, non-invasive screening methodis provided for pre-motor or prodromal Parkinson's disease. The motorfeatures of Parkinson's disease are characterized by muscle rigidity,tremor, gait and postural abnormalities, a slowing of physical movement(bradykinesia) and, in extreme cases, a loss of physical movement(akinesia). The primary symptoms are the results of decreasedstimulation of the motor cortex and other areas of the brain by thebasal ganglia, normally caused by the insufficient formation and actionof dopamine, which is produced in the dopaminergic neurons of the brain.The motor features of Parkinson's disease are just one component of amuch more wide-spread disorder that causes an abundance of non-motorsigns and symptoms, including olfactory dysfunction, REM sleepbehavioral disorder (RBD), constipation, depression, and cognitivedeficits. Importantly, many of these signs and symptoms can precede themotor symptoms by years to a decade or more.

Parkinson's-Like Diseases

There are several other conditions that have the features of Parkinson'sdisease and are interchangeably referred to as Parkinson's-like disease,secondary Parkinsonism, Parkinson's syndrome, or atypical Parkinson's.These are neurological syndromes that can be characterized by tremor,hypokinesia, rigidity, and postural instability. The underlying causesof Parkinson's-like disease are numerous, and diagnosis can be complex.A wide-range of etiologies can lead to a similar set of symptoms,including some toxins, a few metabolic diseases, and a handful of non-PDneurological conditions. A common cause is as a side effect ofmedications, mainly neuroleptic antipsychotics especially thephenothiazines (such as perphenazine and chlorpromazine), thioxanthenes(such as flupenthixol and zuclopenthixol) and butyrophenones (such ashaloperidol (Haldol)), piperazines (such as ziprasidone), and rarely,antidepressants. Other causes include but are not limited toolivopontocerebellar degeneration, progressive supranuclear palsy,corticobasal degeneration, temporo-frontal dementia; drug induced likeantipsychotics, prochlorperazine, metoclopromide; poisoning with carbonmonoxide; head trauma; and Huntington's disease Parkinsonism. In somecases alpha-synucleinopathies can result in Parkinson's-like disease,secondary Parkinsonism, Parkinson's syndrome, or atypical Parkinson's.In a related embodiment the methods described herein are used todiagnose Parkinson's-like disease, secondary Parkinsonism, Parkinson'ssyndrome, atypical Parkinson's, or a alpha syncleinopathy.

Diagnosis or Risk of Neurodegenerative/Neurological Diseases andDisorders

A subject is an animal, including but not limited cows, horses, sheep,cats, dogs, pigs, horses, mice, rats, rabbits, squirrels, non-humanprimates, or humans. In various aspects, a subject is screened todetermine if the subject is suffering from or prone to a neurologicaldisorder such as Parkinson's disease. The screening methods comprisebehavioral, biophysical, biochemical, and imaging assays andobservations as well as questionnaires to determine if the subject is atrisk for or is suffering from the early stages of a neurologicaldisorder (e.g., Parkinson's disease). Biophysical and behavioralobservations, such as physical examination of a subject for outwardsymptoms of disease can be evaluated independently, or combined withquestionnaires and biochemical/imaging assays. Each individual assay canalso be utilized independently or combined with biophysical evaluationsor other tests that are known in the art and associated with aparticular neurological disorder/disease. Examples of biochemical assaysinclude genetic screens for mutations and/or polymorphisms (e.g., SNPsanalysis, short tandem repeat analysis), biomarker-based assays, proteinexpression assays, immunohistochemistry assays or any combinationsthereof. Material for biochemical assays can be sampled from all bodilyfluids and tissues. Commonly employed bodily fluids include but are notlimited to blood, serum, plasma, saliva, urine, gastric and digestivefluid, tears, stool, semen, vaginal fluid, interstitial fluids derivedfrom tumorous tissue, and cerebrospinal fluid. Methods of obtainingsamples of bodily tissue and fluids include but are not limited tobiopsy, cheek swabbing, nose swabbing, rectal swabbing, skin fatextraction or other collection strategies for obtaining a biological orchemical substance.

In some embodiments, screening a subject will include imaging andscanning with the use of, but not limited to Positron EmissionTomography (PET) scans, Magnetic Resonance Imaging (MRI) scans, andSingle-Photon Emission Computerized Tomography (SPECT) scans.Cardiovascular abnormalities related to Parkinson's disease in a subsetof patients can be identified by heart rate spectral analysis.

In certain embodiments, a subject may be screened for early stage,development, or late-stage Parkinson's disease by screening for primaryand secondary symptoms, as described herein immediately following. Inother embodiments the subject may be screened for biochemicalindications of disease e.g., genetic mutations and/or abnormal proteinexpression levels of genes and proteins, respectively, associated with adisorder, in some cases prior to any onset of symptoms such as changesin motor behavior.

Motor (primary) symptoms: There are various factors known in the artwhich are used to screen and diagnose a subject for various neurologicaldisorders. For example, in one embodiment, a subject is examined todetermine if the subject is suffering from Parkinson's disease byassessing presence of primary symptoms which include but are not limitedto: bradykinesia, tremors, rigidity, impaired balance, or a change ingait.

Bradykinesia is slowness in voluntary movement. It produces difficultyinitiating movement as well as difficulty completing movement once it isin progress. The delayed transmission of signals from the brain to theskeletal muscles, due to diminished dopamine, produces bradykinesia.

Tremors in the hands, fingers, forearm, or foot tend to occur when thelimb is at rest but not when performing tasks. Tremor may occur in themouth and chin as well.

Rigidity, or stiff muscles, may produce muscle pain and anexpressionless, mask-like face. Rigidity tends to increase duringmovement.

Poor and impaired balance is due to the impairment or loss of thereflexes that adjust posture in order to maintain balance. Falls arecommon in people with Parkinson's.

Parkinsonian gait is the distinctive unsteady walk associated withParkinson's disease. There is a tendency to lean unnaturally backward orforward, and to develop a stooped, head-down, shoulders-drooped stance.Arm swing is diminished or absent and people with Parkinson's tend totake small shuffling steps (called festination). Someone withParkinson's may have trouble starting to walk, appear to be fallingforward as they walk, freeze in mid-stride, and have difficulty making aturn.

In some embodiments, the Hoehn and Yahr staging is used in diagnosis ofprimary symptoms in a subject. The Hoehn and Yahr scale is a commonlyused system for describing how the symptoms of Parkinson's diseaseprogress (Hoehn M, Yahr M (1967). “Parkinsonism: onset, progression andmortality” Neurology 17 (5): 427-42). The scale allocates stages from 0to 5 to indicate the relative level of disability.

-   Stage 1: Symptoms on one side of the body only.-   Stage 2: Symptoms on both sides of the body. No impairment of    balance.-   Stage 3: Balance impairment. Mild to moderate disease. Physically    independent.-   Stage 4: Severe disability, but still able to walk or stand    unassisted.-   Stage 5: Wheelchair-bound or bedridden unless assisted.

In other embodiments, the Unified Parkinson's Disease Rating Scale(UPDRS) is used in the diagnosis of a subject. The UPDRS is a ratingtool to follow the course of Parkinson's disease. It is made up ofthe 1) Mentation, Behavior, and Mood, 2) Activities of Daily Living and3) Motor sections. These are evaluated by interview. Some sectionsrequire multiple grades assigned to each extremity. A total of 199points are possible. 199 represents the worst (total) disability), 0—nodisability.

In other embodiments, the Schwab and England Activities of Daily Livingassessment can be used in the diagnosis of a subject. The subject isassigned a rating from 0% to 100%. Rating can be assigned by rater or bysubject.

Non-motor (secondary) symptoms: In some embodiments, progressive loss ofvoluntary and involuntary muscle control produces a number of secondarysymptoms associated with Parkinson's disease. In some embodiments thesesymptoms are indicative of onset of primary symptoms. In otherembodiments secondary symptoms can be in the absence of diagnosablemotor symptoms, or present with primary symptoms. These symptoms candevelop well before, shortly before, during, or after the onset anddevelopment of primary symptoms. In some cases, a subject can experienceand display these symptoms about 50, 40, 30, 20, 15, 10, 5, 2 years, 1year or 6 months before or 6 months, 1, 2, 5, 10, 15, 20, 30, 40, ormore years after onset and display of primary symptoms. Some patientsdevelop these secondary symptoms well before, years before the patientsdevelop primary symptoms characteristic with a disorder. Some secondarysymptoms of Parkinson's disease include but are not limited to thefollowing: Constipation occurring in a subject's 20's, 30's 40's or50's; difficulty swallowing (dysphagia), saliva and food that collectsin the mouth or back of the throat may cause choking, coughing, ordrooling; excessive salivation (hypersalivation), excessive sweating(hyperhidrosis), loss of bladder and/or bowel control (incontinence);loss of sense of smell, olfactory dysfunction (anosmia); rapid eyemovement (REM) sleep behavior disorder and other sleep disorders;changes in the cardiac sympathetic denervation, changes in thesympathetic innervation of the heart; loss of intellectual capacity(dementia), psychosocial: anxiety, depression, isolation; scaling, dryskin on the face and scalp (seborrhea); slow response to questions(bradyphrenia); small, cramped handwriting (micrographia); soft,whispery voice (hypophonia), and fatigue.

Therefore, in certain embodiments, diagnosis is based on symptoms andruling out other disorders that produce similar symptoms. However tomake a diagnosis of typical Parkinson's disease, a subject must have twoor more of the diagnosable motor symptoms, one of which is a restingtremor or bradykinesia. In many cases, this diagnosis is made afterobserving that symptoms have developed and become established over aperiod of time. Such diagnostic techniques described above are known inthe art.

After a thorough neurological exam and medical history, the neurologistmay order computerized tomography (CT scan) or magnetic resonanceimaging (MRI scan) to meet the other criterion for a diagnosis ofParkinson's disease: ruling out disorders (e.g., brain tumor, stroke)that produce Parkinson's-like symptoms. Some examples follow:medications—antipsychotics (e.g., Haldol) and anti-emetics (e.g.,Compazine); multiple strokes; hydrocephalus; progressive supranuclearpalsy—degeneration of midbrain structures; Shy-Drager syndrome—atrophyof central and sympathetic nervous systems; Wilson's disease—copperexcretion causes degeneration of the liver and basal ganglia; Bloodand/or cerebrospinal fluid (CSF) analysis may be ordered to look forspecific abnormalities associated with other disorders.

In some embodiments, diagnosis is based on secondary non-motor symptomseven when the subject show no or very few of the primary motor symptomsassociated with the neurological disease.

In some embodiments, the secondary symptom or non-motor is selected fromthe group consisting of rapid eye movement sleep behavioral disorder,olfactory dysfunction, cardiac sympathetic denervation, constipation,depression, anxiety and dementia. In some embodiments, the secondarysymptom is a sleep disorder.

Therefore, where primary and secondary symptoms are insufficient toindicate disease onset, a genetic/biochemical or other type of screencan be conducted to determine if the subject is at risk for developing aneurological disorder (e.g., Parkinson's disease or Alzheimer'sdisease).

Heart Rate Variability (HRV) in Prodromal/Pre-Motor Parkinson's Diseaseor Parkinson's-Like Disease

In one embodiment, the present invention provides a method of assessingwhether a population of patients has prodromal/pre-symptomatic/pre-motorParkinson's disease or Parkinson's-like disease. In some embodiments,the patients present with a REM sleep behavior disorder (RBD). In someembodiments, REM sleep behavior disorder (RBD) with no obvious evidenceof Parkinson's disease or Parkinson's-like disease or dementia with Lewybodies (DLB) is studied. RBD is a parasomnia with loss of muscle atoniaduring REM sleep resulting in enactment of dreams (Ferini-Strambi et aland Olson et al.) and is associated with alpha-synucleinopathies (Olsonet al., Stiasny-Kolster et al. Boeve et al) such as Parkinson's diseaseor Parkinson's-like disease, Dementia with Lewy Bodies (DLB) andMultiple System Atrophy (MSA). RBD may precede and predict the clinicalsymptoms of typical Parkinson's disease or Parkinson's-like disease byyears to a decade or more. Up to 65% of patients with pure RBD willeventually develop Parkinson's disease, Parkinson's-like disease, or arelated synucleinopathy.

Subjects with REM sleep behavioral disorder (RBD) can have significantalterations in heart rate variability (HRV) as measured byelectrocardiogram tracings compared to a group of age matched controlswithout RBD. In some embodiments, EKG is used to identify changes in HRVin individuals with RBD with possible “pre-motor” or prodromalParkinson's disease or Parkinson's-like disease. In some embodiments, aroutine EKG is used as a simple, non-invasive, and low-cost screeningtool for pre-motor/prodromal Parkinson's disease or Parkinson's-likedisease that can be incorporated into routine physical examinations ofindividuals. In some embodiments, the individuals going through thephysical examination with a routine EKG for screening pre-motorParkinson's disease or Parkinson's-like disease are in the 50s andbeyond. In some embodiments, Lewy bodies have been observed in thesuperior sympathetic ganglia at least 10 years before the diagnosis ofParkinson's disease or Parkinson's-like disease. Furthermore, cardiacLewy neuritic pathology has been found in most if not all cases ofincidental Lewy body cases (presumable Braak Stage I and II Parkinson'sdisease or prodromal Parkinson's disease).

In some embodiments, the EKG result comprises a heart rate variability(HRV) result. The HRV result may comprise a time domain measure. Themeasure can be selected from the group consisting of standard deviationof R-R intervals (SDNN), the standard deviation of the heart rate(SDHR), the root mean square difference of successive RR intervals(RMSSD), and the percentage number of consecutive RR intervals differingby more than 50 msec (pNN50). In some embodiments, the EKG result isobtained for at least 1 minute, at least 2 minutes, at least 3 minutes,at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8minutes, at least 9 minutes, at least 10 minutes, at least 15 minutes,at least 20 minutes, at least 3-5 minutes, at least 5-10 minutes, or atleast 15-20 minutes.

In some embodiments, the HRV result comprises a geometric/non-linearmeasure. These include measures derived from the Poincaré plot, which isa graphical representation of the relationship between consecutive RRintervals, where an RR interval is plotted against the preceding RRinterval. The short term HRV (beat-to-beat) is calculated perpendicularto the line of identity (SD1) and the long term (overall HRV) iscalculated along the line of identity (SD2). Geometric measures includeRR triangular index and the triangular interpolation of NN (TINN).

In some embodiments, the HRV result comprises a frequency domainmeasure, e.g., Very Low Frequency (VLF) (0-0.04 Hz), Low Frequency (LF)(0.04-0.15 Hz), or High Frequency (HF) (0.15-0.4 Hz). The values can bereported in both absolute values and normalized units. In someembodiments, the frequency domain measures include Total Power and theLF/HF ratio.

In another aspect, the present invention provides a method for screeninga subject for a neurological disorder comprising, (a) obtaining datafrom a subject wherein the data are associated with one or moreparameter related to the neurological disorder to produce an analysisresult; (b) comparing the analysis result to information from a control,wherein the information is predetermined to indicate absence of theneurological disorder.

In another aspect, the present invention provides a method of screeninga subject for Parkinson's disease or Parkinson's-like disease bymeasuring cardiac autonomic denervation as one pathway to achieve largescale screening of the general population for Parkinson's disease orParkinson's-like disease. Cardiac autonomic denervation (CAD) is a nearuniversal feature in Parkinson's disease or Parkinson's-like diseasewhen the motor signs are fully evident. Additionally, CAD may precedemotor dysfunction in Parkinson's disease or Parkinson's-like disease assuggested by the presence of Lewy bodies in the superior sympatheticganglia many years prior to diagnostic Parkinson's disease and in thecardiac plexus in 100% of Parkinson's and incidental Lewy body diseasecases. CAD results in reduced HRV and is documented in patients withclinically diagnosable Parkinson's disease. In one embodiment, an easy,non-invasive method of measuring CAD is by heart rate variability (HRV),which can be assessed using a standard electrocardiogram (EKG). Sincepatients with pre-motor/prodromal Parkinson's disease and/orParkinson's-like disease may have CAD, this abnormality can beidentified by measuring HRV. In some embodiments, HRV is used as amarker to assess RBD. HRV can be measured during wakefulness or duringsleep.

In one embodiment, cardiac sympathetic denervation (CSD), a feature inParkinson's disease, is observed in presymptomatic Parkinson's diseaseand/or Parkinson's-like disease. In some embodiments, CSD is observedusing imaging agents including but not limited to iodine-123metaiodobenzylguanidine and fluorodopa positron emission tomographyimaging and by cardiac catheterization. CSD reduces heart ratevariability (HRV), which can be assessed using a standardelectrocardiogram (EKG). Reduced HRV is observed in patients withalready diagnosed Parkinson's disease. CSD is documented by assessingchanges in HRV in a population that has a high probability of havingpre-motor Parkinson's disease or Parkinson's-like disease, i.e.,patients with RBD. In some embodiments, the present invention'sscreening method for pre-motor/prodromal Parkinson's disease orParkinson's-like disease is incorporated into annual physicalexaminations.

In other embodiments of the invention, other non-motor features ofParkinson's disease or Parkinson's-like disease are analyzed, includingtesting of changes in sense of smell and evaluation for other featuressuch as autonomic dysfunction, and changes in mood and cognition.Therefore, in re-evaluation of all RBD patients for other features ofParkinson's disease or Parkinson's-like disease, individuals who havesubsequently developed Parkinson's disease or Parkinson's-like diseaseare identified, thereby providing supporting evidence that they hadpre-motor/prodromal Parkinson's disease or Parkinson's-like disease atthe time of their sleep recordings.

In some embodiments, the subject of the present invention is in awakeful state or awake while obtaining the EKG result. In someembodiments, the subject has been diagnosed with a REM sleep behavioraldisorder (RBD). In some embodiments, the HRV result comprises afrequency domain measure, e.g., Very Low Frequency (VLF) (0-0.04 Hz),Low Frequency (LF) (0.04-0.15 Hz), or High Frequency (HF) (0.15-0.4 Hz).The values can be reported in both absolute values and normalized units.In some embodiments, the frequency domain measures include Total Powerand the LF/HF ratio. In some embodiments, the subject has a lower RMSSDthan a subject not having an EKG result falling into an EKG result rangepredetermined to be indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has a lowerpNN50 than a subject without having an EKG result falling into an EKGresult range predetermined to be indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has a lowerSDNN than a subject without having an EKG result falling into an EKGresult range predetermined to be indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has a lowerSD1 than a subject without having an EKG result falling into an EKGresult range predetermined to be indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has a lowerSD2 than a subject without having an EKG result falling into an EKGresult range predetermined to be indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has a lowerRR triangular index than a subject without having an EKG result fallinginto an EKG result range predetermined to be indicative of Parkinson'sdisease or Parkinson's-like disease. In some embodiments, the subjecthas a lower TINN number than a subject without having an EKG resultfalling into an EKG result range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower VLF(ms²) than a subject without having an EKGresult falling into an EKG result range predetermined to be indicativeof Parkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower LF(ms²) than a subject without having an EKGresult falling into an EKG result range predetermined to be indicativeof Parkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower HF(ms²) than a subject without having an EKGresult falling into an EKG result range predetermined to be indicativeof Parkinson's disease or Parkinson's-like disease. In some embodiments,the subject has a lower Total Power(ms²) than a subject without havingan EKG result falling into an EKG result range predetermined to beindicative of Parkinson's disease or Parkinson's-like disease. In someembodiments, the subject being screened by the method of the presentinvention has not been previously diagnosed as having Parkinson'sdisease or Parkinson's-like disease. In some embodiments, the subjectdoes not exhibit any motor symptoms indicative of Parkinson's disease orParkinson's-like disease. In some embodiments, the subject has beenassessed to be 0 on the Hoehn and Yahr scale. In some embodiments, thesubject has not been assessed on the Hoehn and Yahr scale. In someembodiments, the subject has been assessed to be 0 on the UnifiedParkinson's disease rating scale (UPDRS). In some embodiments, thesubject has not been assessed on the UPDRS scale. In some embodiments,the subject further has a symptom including but not limited toconstipation, olfactory dysfunctions, autonomic disturbances such asdysautonomia, psychological symptoms such as depression, and sleepdisorders such as RBD. In some embodiments, the subject furtherundergoes genetic testing for Parkinson's disease or Parkinson's-likedisease. In some embodiments, the subject further undergoes brainimaging. The brain imaging can be PET or MRI. In some embodiments, thesubject is considered for inclusion into a clinical trial. In someembodiments, the subject is prescribed a neuroprotective agent ortherapy. One therapy to prevent or delay onset of Parkinson's disease orParkinson's-like disease is exercise. Some neuroprotective therapiesoffer protection against cell degeneration to the neuronal cells. Otherneuroprotective agents specifically protect the dopamine neurons. Themajority of neuroprotective agents are antioxidants. Animmunosuppressive calcineurin inhibitor, NOS inhibitor, sigma-1modulator, AMPA antagonist and Ca2+ channel blocker have all shownneuroprotective activity. An estrogen agonist and two glycoproteinIIb/IIIa antagonists also exhibit neuroprotective activity.Neuroprotective agents that can be used in the present invention includebut are not limited to erythropoietin, astaxanthin, boswellia, caffeine,curcumin, E vitamins as tocotrienols, flavonoids, grapefruit juice(naringenin), huperzine and ubiquinol. Other disease modifying agentssuch as MAO inhibitors, calcium channel blockers, kinase inhibitors,mitochondrial modulators/enhancers, alpha synuclein modulators can beused in the methods described herein.

It will be evident, that various risk factors known for a neurologicaldisorder can be utilized to screen a subject, in order to determinewhether the subject is at risk of developing the particular neurologicaldisorder. Therefore, in various embodiments, such neurological disordersinclude, but are not limited to, ADHD, Alzheimer's disease (AD),amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), Bell's Palsy,Cerebral Palsy, chemotherapy-induced neuropathies (e.g., fromvincristine, paclitaxel, bortezomib), chorea-acanthocytosis,Creutzfeldt-Jakob Disease (CJD), progressive supranuclear palsy,corticobasal degeneration, fronto-temporal dementia, dementia,diabetes-induced neuropathies, diffuse Lewy body disease, Epilepsy,Essential Tremor, Friedreich's ataxia, Guillain-Barre Syndrome,Hemifacial Spasm, Huntington's disease (HD), Movement Disorders,Multiple Sclerosis, Multisystem Atrophy (MSA), Nervous System Tumors,Neurofibromatosis, Neuropathy, ocular diseases (ocular neuritis),Parkinson's disease (PD), Periodic Limb Movement Disorder, primarylateral sclerosis, Seizure Disorders, Tourette's Syndrome or TraumaticBrain Injury. In some embodiments, a subject is at risk of developing oris suffering from Parkinson's disease or Parkinson's-like disease,Alzheimer's Disease or a Neuropathy. In other embodiments, a subject issuffering from the early stages of Parkinson's disease orParkinson's-like disease, Alzheimer's Disease or a Neuropathy.

In some embodiments, the parameters related to the neurologicaldisorders include but are not limited to olfactory dysfunction, REMsleep behavioral disorder (RBD), constipation, depression, cognitivedeficits, heart rate variability or a combination thereof.

In another aspect, the present invention provides an algorithm forcomparing the EKG result from a subject undergoing the screening forParkinson's disease or Parkinson's-like disease to an EKG result rangepredetermined to be indicative of Parkinson's disease orParkinson's-like disease. The algorithm can be used to determine if theEKG result from the subject falls in the EKG result range, therebydetermining whether the subject is suffering from or prone toParkinson's disease or Parkinson's-like disease.

In yet another aspect, the present invention provides kits for carryingout the method of the present invention. The kit may include materialsto test for the predisposition of a neurological disorder, e.g.Parkinson's disease or Parkinson's-like disease. In some embodiments,the kits include reagents and instruments for measuring EKG of a subjectundergoing the screening for Parkinson's disease or Parkinson's-likedisease. The kits further comprise suitable packaging, and writtenmaterial that can include instructions for use, discussion of clinicalstudies, listing of side effects, and the like. The kit may furthercontain a neuroprotective agent. The kit may further include materialfor olfactory testing. In some embodiments, the reagents, instrumentsand the other agents are provided as separate compositions in separatecontainers within the kit.

Genetic Screening

As indicated herein above, screening a subject to determine if thesubject is at-risk for developing a neurological disorder such asParkinson's disease or Parkinson's-like disease can be based on imaging,behavior, biophysical and/or biochemical screening for traits/factorsassociated with a neurological disorder/disease. In one such aspect ofthe invention, a biochemical screening involves genetic testing.Therefore, in various embodiments of the invention, a method of treatinga subject at risk of a neurological disorder comprises screening geneticmaterial from the subject to determine if markers are present (e.g.,mutations of genes, expression levels of proteins) associated with theneurological disorder or pre-motor/prodromal symptoms of the disorder,thereby determining risk, and administering a compound (or a combinationof two or more compounds) that inhibits, decreases, reverses, orprevents α-synuclein fibrillation and/or aggregation, or induces kinaseinhibition, or induces MAO inhibition, or acts as a calcium channelblocker, or as a mitochondrial enhancer to the subject to delay orreduce progression of a neurological disorder. The disorder may be atthe early onset stage or the subject may be entirely asymptomatic. Forexample, to determine if a subject is at risk for Parkinson's disease,the subject can be screened for mutations of one or more LRRK2,α-synuclein, parkin gene or a combination of two or more markersthereof. Furthermore, the subject can be screened for elevatedexpression levels of a protein indicative of disease onset or risk fordisease. Methods of performing such genetic/biochemical screens areknown in the art.

In some embodiments, the subject is screened for a mutation in a geneselected from the group consisting of leucine-rich repeat kinase 2(LRRK2), α-synuclein (SNCA), parkin (PRKN), ubiquitin C-terminalhydrolase L1 (UCH-L1), oncogene DJ-1 gene, PTEN-induced protein kinase 1(PINK1), and microtubule-associated protein tau (MAPT). Such mutationsinclude but are not limited to substitution, deletion, insertion,duplication, triplication or a combination thereof.

LRRK2. In one embodiment, the subject is pre-symptomatic of primarysymptoms for Parkinson's disease, but genetic screening yieldsinformation on the presence mutations and/or polymorphisms of one ormore genes associated with Parkinson's disease. For example, a subjectis screened for the prevalence of two common leucine-rich repeat kinase2 (LRRK2) gene mutations. Patients with LRRK2 mutations have showntypical levodopa responsive Parkinson's disease with tremor being themost common presenting feature. Patients with the G2019S mutation haveshown a similar age of onset of symptoms when compared with patientswith other LRRK2 mutations or sporadic Parkinson's disease, and can bemore likely to have a family history of Parkinson's disease. Inaddition, a familial A1442P (4,324 G>C) mutation has been observed.Therefore, in one embodiment, a subject is tested to determine thepresence of LRRK2 mutations and if positive for such mutations, thesubject is administered one or more therapies that inhibit, decrease,reverse, or prevents α-synuclein fibrillation and/or aggregation,inhibits MAO, inhibits kinases, blocks calcium channels, enhancesmitochondrial function as a prophylactic to delay, reduce or eliminateParkinson's disease onset or progression.

α-synuclein. In other embodiments, genetic screens detect the presenceof α-synuclein gene mutations or multiplications and/or polymorphismswhich are major underlying genetic defects known in familial juvenileonset Parkinson's disease, and α-synuclein is a major constituent ofLewy Bodies, the pathological hallmark of Parkinson's disease.

Mutations in, or over-expression of, α-synuclein may cause damage byinterfering with particular steps of neuronal membrane traffic.α-synuclein selectively blocks endoplamic reticulum (ER)-to-Golgitransport, thus causing ER stress. α-synuclein may serve a chaperonefunction for the proper folding of soluble NSF attachment receptor(SNAREs) that are important for neurotransmitter release.

Therefore in some embodiments, a subject is diagnosed or pronounced tobe at-risk after a genetic screen to determine the presence ofα-synuclein mutations and/or polymorphisms and/or detection of elevatedexpression levels of α-synuclein, wherein mutations and/or polymorphismsand/or elevated expression levels are indicative of risk of Parkinson'sdisease. Further, the subject may be optionally examined for display ofone or more secondary symptoms. Thus, in one such embodiment, thesubject is administered one or more therapies that inhibit, decrease,reverse, or prevent α-synuclein aggregation and fibrillation and/oraggregation, or inhibits kinases such as LRRK kinase, or inhibits MAO,or acts as a calcium channel blocker, or a mitochondrial enhancer as aprophylactic to delay, reduce or eliminate Parkinson's disease and/orParkinson's-like disease onset or progression.

In another embodiment, a subject is screened for LRRK2 mutationsdescribed above and α-synuclein mutations and/or polymorphisms and/oroverexpression, where positive results (e.g., mutations, overexpression)are indicative of risk of developing Parkinson's Disease, and thesubject is treated with one or more therapies that inhibit, decrease,reverse, or prevents α-synuclein fibrillation and/or aggregation orinhibits kinases such as LRRK kinase, or inhibits MAO, or acts as acalcium channel blocker, or a mitochondrial enhancer as a prophylacticto delay, reduce or eliminate Parkinson's disease and/orParkinson's-like disease onset or progression.

Parkin gene. In another embodiment, a subject is genetically screened todetermine if one or more parkin gene mutation and/or polymorphism ispresent to determine risk for Parkinson's Disease. If one or more parkingene(s) are mutated or have a polymorphism associated with aneurological disease then the subject can be treated with a compoundnamed herein. People with one mutation may develop the disease 12 yearsearlier than average. Two mutated genes are linked with disease whichstarts 13 years earlier. The prevalence of Parkinson's increases withage—appearing in 1% of people over 60 and 4-5% of those over 85—but itcan develop in much younger patients. Inheriting mutations, deletions,or multiplications of the parkin gene is associated with the developmentof early-onset Parkinson's—which refers to disease which appears beforethe age of 50.

Therefore, in prophylactic treatment methods of the invention, a subjectundergoes genetic screen to determine risk for Parkinson's disease(e.g., presence of one or two PRKN mutations) and if found to beat-risk, is administered one or more compound that inhibits, decreases,reverses, or prevents α-synuclein fibrillation and/or aggregation. Insome further embodiments, a subject may be screened for PRKN and LRRK2mutations and/or polymorphisms to determine if a prophylacticadministration of one or more therapies described herein that inhibits,decreases, reverses, or prevents α-synuclein fibrillation and/oraggregation, or inhibits kinases such as LRRK kinase, or inhibits MAO,or acts as a calcium channel blocker, or a mitochondrial enhancer as aprophylactic to delay, reduce or eliminate Parkinson's disease and/orParkinson's-like disease onset or progression is desirable. In any ofthe genetic screens described herein, the presence of mutations and/orpolymorphisms in one familial gene should not serve as exclusioncriteria in a screen for further genetic variation.

In certain embodiments, a subject may be routinely screened formutations and/or polymorphisms, to determine if at risk and determine ifa prophylactic administration of one or more compounds described hereinthat inhibits, decreases, reverses, or prevents α-synuclein fibrillationand/or aggregation, or inhibits kinases such as LRRK kinase, or inhibitsMAO, or acts as a calcium channel blocker, or a mitochondrial enhanceras a prophylactic to delay, reduce or eliminate Parkinson's diseaseand/or Parkinson's-like disease onset or progression is desirable. Inother embodiments, a subject may be first screened and secondarynon-motor symptoms identified, determined to be at risk, and furtherscreened for mutations and/or polymorphisms to determine if aprophylactic administration of one or more therapies described hereinthat inhibits, decreases, reverses, or prevents α-synuclein fibrillationand/or aggregation, or inhibits kinases such as LRRK kinase, or inhibitsMAO, or acts as a calcium channel blocker, or a mitochondrial enhanceras a prophylactic to delay, reduce or eliminate Parkinson's diseaseand/or Parkinson's-like disease onset or progression is desirable.

Parkinson's Disease or Parkinson's-Like Disease Therapies

Parkinson's disease is a chronic disorder for which no cure is currentlyknown and existing medications and therapies provide transient relieffrom the primary motor-related symptoms but may not always be diseasemodifying.

Levodopa (L-dopa) is used as a form of symptomatic treatment. L-dopa istransformed into dopamine in the dopaminergic neurons by L-aromaticamino acid decarboxylase. However, only 1-5% of L-dopa enters thedopaminergic neurons. The remaining L-dopa is often metabolized todopamine elsewhere, causing a wide variety of side effects. Due tofeedback inhibition, L-dopa results in a reduction in the endogenousformation of L-dopa, and so eventually becomes counterproductive.Carbidopa and benserazide are dopa decarboxylase inhibitors. They helpto prevent the metabolism of L-dopa before it reaches the dopaminergicneurons and are generally given as combination preparations ofcarbidopa/levodopa (co-careldopa) and benserazide/levodopa(co-beneldopa). Duodopa is a combination of levodopa and carbidopa.

The dopamine agonists bromocriptine, pergolide, pramipexole, ropinirole,cabergoline, apomorphine, and lisuride are moderately but onlytransiently effective when utilized for symptomatic treatment. Dopamineagonists can be useful for patients experiencing on-off fluctuations anddyskinesias as a result of high doses of L-dopa.

MAO-B inhibitors (first, second, or later generation MAO-B inhibitors)reduce the symptoms associated with Parkinson's disease by inhibitingthe breakdown of dopamine secreted by the dopaminergic neurons. Anexemplary MAO-B inhibitor is Rasagiline [N-propargyl-1(R)-aminoindan], asecond-generation propargylamine pharmacophore that selectively andirreversibly inhibits brain MAO-B.

Noradrenergic drugs such as norepinephrine may be useful in preventing,reversing, or treating early premotor/prodromal Parkinson's disease orParkinson's-like disease.

Kinase inhibitors such as p38 mitogen-activated protein kinaseinhibitors, mixed lineage kinase inhibitors, (for example CEP-1347),Leucine-rich Repeat Kinase 2 (LRRK2) inhibitors may be useful inpreventing, reversing, or treating early premotor/prodromal Parkinson'sdisease or Parkinson's-like disease.

Mitochondrial modulators such as Enzyme co-Q10 may be useful inpreventing, reversing, or treating early premotor/prodromal Parkinson'sdisease or Parkinson's-like disease.

Calcium channel blockers such as isradipine may be useful in preventing,reversing, or treating early premotor/prodromal Parkinson's disease orParkinson's-like disease.

Increased exercise may be useful in preventing, reversing, or treatingearly premotor/prodromal Parkinson's disease or Parkinson's-likedisease.

Compounds that prevent/reverse/disaggregate, halt aggregation ofalpha-synuclein may be useful in preventing, reversing, or treatingearly premotor/prodromal Parkinson's disease or Parkinson's-likedisease. Such compounds are described and listed in WO/2009/003147, thepublication is hereby incorporated in its entirety.

In some embodiments, a subject who has been diagnosed to have prodromalor pre-motor Parkinson's disease or Parkinson's-like disease using themethod of the present invention can be treated with a prophylactic drugor other therapy such as exercise. A prophylactic drug for Parkinson'sdisease or Parkinson's-like disease is a drug taken to maintain healthand prevent or delay the onset of Parkinson's disease orParkinson's-like disease. For example, such subject can be administereda compound that inhibits, decreases, reverses, or prevents α-synucleinfibrillation and/or aggregation as a prophylactic measure. In otherembodiments, such subject can be given gene therapy. For example, anadeno-associated virus can be used to transport a gene that codes forthe enzyme glutamic acid decarboxylase (GAD) into the neurons of thesubthalamic nucleus. The gene prompts these subthalamic cells to producegamma-aminobutyric acid (GABA), the brain's primary inhibitoryneurotransmitter, which decreases the activity in the subthalamicnucleus, a brain area that tends to be extremely overactive inParkinson's patients, thereby restoring the normal motor function. Otherexperimental techniques for treatment of neurodegenerative disordersinclude stem cells transplants and upregulation of a molecule thatprevents neurodegeneration.

EXAMPLES Example 1

Subjects and Archived Data: Archived data of 45 individuals diagnosedwith RBD in addition to 45 age and gender-matched insomnia patients ascontrol subjects are analyzed. Complete, one-night polysomnographyevaluations would have already been completed in all of theseindividuals. The data from these studies are stored in an electronicallyretrievable and analyzable form, including continuous EKG recordings. Inalternative embodiments, data are obtained from subjects screened anddiagnosed for RBD.

Diagnosis and inclusionary criteria: All charts and sleep recordingsfrom this cohort of RBD patients is first subjected to a structured andsystematic restoring to confirm a diagnosis of RBD. The InternationalClassification of Sleep Disorders, Second edition (ICSD-2) is used asthe diagnostic criteria for RBD. Those subjects meeting the diagnosticcriteria after re-scoring are included in this project.

Control subjects: Polysomnograms from age- and sex-matched patients withinsomnia, who do not have any other conditions that could affect HRV(neurodegenerative or cardiovascular diseases, diabetes, certainmedication etc.), are selected as control subjects.

Data retrieval and analysis: Data are collected using the ‘SandmanElite®’ sleep diagnostic system. This system collects patientelectrophysiological data, including EKG, and saves them digitally on acomputer. All data are de-identified of personal or confidentialinformation. REM sleep portions of the EKG are selected for each subject(RBD patients and insomnia controls) since this is the sleep phase whenthere is the most variability in heart rate; furthermore it is the timeduring sleep that most resembles wakefulness physiologically. A fiveminute EKG segment under stable conditions (stable breathing and no legmovements) is visually identified and the beat-to-beat (R-R) intervaldata for this period is manually selected and saved for further HRVanalysis.

HRV Analysis tools: The R-R interval is used as the input to a freesoftware program developed for the study of HRV by the University ofKuopio, Finland. This program calculates all of the time and frequencydomain parameters commonly used in HRV analysis. Graphicalrepresentations in the form of Poincaré plots and parametric andnon-parametric spectral estimates are also generated.

Parameters to be evaluated: HRV is influenced by both the sympatheticand parasympathetic nervous system and can be assessed with time andfrequency domain methods. Time domain measures of HRV used are the mean,the standard deviation of R-R intervals (SDNN), and the percentagenumber of consecutive RR intervals differing by more than 50 msec(pNN50).

In the frequency domain, Power Spectral Density of the three frequencybands of HRV are Very Low Frequency, VLF (0-0.04 Hz), Low Frequency, LF(0.04-0.15 Hz), High Frequency, HF (0.15-0.4 Hz). LF/HF ratio is alsocalculated. The HF band is related to respiration and considered to beparasympathetically mediated. LF is influenced both by the sympatheticand parasympathetic components. VLF involves thermoregulatory andperipheral vascular mechanisms. The nonlinearities in HRV aregraphically represented by the Poincaré plot which shows the correlationbetween consecutive RR intervals.

Statistical Analysis: Statistical analysis is performed on the twogroups (RBD patients and controls). The various time and frequencyparameters are analyzed for their statistical significance using aparametric method. Based on literature values of R-R variability innormal subjects, RBD and Parkinson's disease or Parkinson's-like diseasepatients, a power analysis yielded a sample size of 20 subjects for eachgroup to be adequate to achieve 80% power for all variables. Based onalpha of 0.05 and our sample size of 45 subjects in each group, even ifonly half of the subjects have pre-motor Parkinson's disease orParkinson's-like disease, there is enough statistical power to detectdifferences in the two groups.

A statistically significant decrease is observed in HRV in RBD patientscompared to insomnia controls. In addition, the analysis allows thesearch for other cardiac variables that might separate RBD patients fromcontrols. Patients with insomnia are used as controls, as this grouppresents the least deviation in HRV from normal subjects. As a secondaryanalysis, RBD patients are compared against standardized data from theliterature. In order to eliminate any data transfer issues, a “proof ofprinciple” assessment was conducted by going step by step through theentire process of data transfer and analysis with data from threerandomly selected subjects, and have successfully completed the processin all three instances. One of these patients showed a near completeloss of HRV as expected (FIG. 1). The figure shows the scatter plot (thePoincaré plot) of the current R-R interval (RRI_(n+1) (s)) plottedagainst the preceding R-R interval (RRI_(n) (s)) for a control subject(top) as well as that for an RBD patient (bottom). The scatter for thecontrol subject is large indicating a large R-R variability. Thisdenotes a balanced autonomic function. The scatter for the RBD patientis minimal, indicating very little variability in R-R intervals. Thisdenotes autonomic denervation similar to that of a heart transplantpatient. Thus, in this particular RBD patient the autonomic denervationis severe.

EKGs during quite wakefulness are also obtained for comparativeanalysis.

Example 2 Assessment of Heart Rate Variability During Wakefulness inPatients with RBD

A retrospective case-control study of 11 RBD patients and 11 controlsubjects without RBD was performed. Heart rate variability (HRV)analysis was performed from the R-R intervals during wakefulness. Thesewere obtained from pre-sleep segment of electrocardiogram (EKG) channelof one night polysomnography.

Methods:

Subjects and Archived Data: The EKG tracings of patients undergoingpolysomnography (PSG) from the year 2000 through 2008 were analyzed. Allpatients diagnosed with RBD during this period were identified through asearch of the medical records. Age and gender-matched patientsundergoing PSGs for insomnia during the same period were identified andused as control subjects.

Diagnosis and inclusionary criteria: All clinic patient charts and sleeprecordings from this cohort of RBD patients were systematically rescoredat the SSDC to confirm a diagnosis of RBD. The InternationalClassification of Sleep Disorders, Second edition (ICSD-2) was used asthe diagnostic criteria for RBD. Only RBD subjects who showed PSGabnormality typical of RBD after rescoring and also exhibited clinicalsymptoms compatible with dream-enacting behavior were included. Thus,those presenting subclinical RBD (typical PSG findings but no reportedclinical symptoms) were, excluded. Other exclusionary factors includedcardiovascular disease, significant arrhythmias, diabetes, otherneurological disorders, or other sleep disorders such as narcolepsy, orcurrent use of medications that are known to influence autonomicfunction. RBD patients=11 (mean age 63.27±7.46 years).

Control subjects: Because polysomnogram (PSG) from a normal controlpopulation were unavailable, polysomnograms from age- and sex-matchedpatients with insomnia evaluated at SSDC, who did not have any otherconditions that could affect HRV, were selected as the control subjects.Although not selected from the general population, subjects withinsomnia are not typically known to have associate neurological diseaseand/or autonomic dysfunction. Therefore, this group was very close incardiac autonomic function during wakefulness to that of normalindividuals. Eleven control subjects (7 men and 4 women) were includedin the study (mean age 59.45±8.66).

Data retrieval and analysis: All data were originally collected andstored using the ‘Sandman Elite®’ (Sandman Elite Sleep DiagnosticSoftware User's manual) sleep diagnostic system at the SSDC. This systemcollects a wide variety of electrophysiological data, including EKG, andsaves them digitally on a computer. Data from PSG recordings ofindividuals with iRBD and controls meeting inclusion/exclusion criteriawere de-identified by SSDC personnel and provided to the Parkinson'sInstitute (TPI) for analysis. One night polysomnogram (PSG) recordingswere obtained. For the purpose of analysis, a period of data when thesubjects were awake, i.e. before sleep onset, was required. In order toobtain a data segment during wakefulness, a period was identified on thepolysomnogram that was after bio-calibration but before occurrence ofone of the sleep stages, thus ensuring that all data analyzed were wellbefore sleep onset. A 5-minute portion of the EKG during wakefulness andunder stable conditions (stable breathing and no leg movements) was thenvisually identified during this period for each subject (RBD patientsand insomnia controls). Any ectopic beats that occurred were manuallyremoved and the beat-to-beat (R-R) interval data for this period wassaved for further HRV analysis.

HRV Analysis tools: The normal to normal (i.e. those resulting fromsinus node depolarization) R-R interval was used as the input to a freesoftware program developed for the study of HRV by the University ofKuopio, Finland by Niskanen et al. This program was used to calculateall of the time and frequency domain parameters commonly used in HRVanalysis. Graphical representations in the form of Poincaré plots andparametric and non-parametric spectral estimates were also computed.

Parameters evaluated: HRV is an easily derived measure of cardiacautonomic activity. It is a reliable quantitative marker of autonomicnervous system activity and can be assessed with time and frequencydomain methods. HRV can be quantified in terms of various measures thathave been well established to be influenced by either the sympathetic orparasympathetic nervous system or is an indicator of sympathovagalbalance.

One simple way of evaluating HRV is by the time domain measures. In thisexample, the standard deviation of R-R intervals (SDNN), the standarddeviation of the heart rate (SDHR), the root mean square difference ofsuccessive RR intervals (RMSSD), and the percentage number ofconsecutive RR intervals differing by more than 50 msec (pNN50) wereused. SDNN indicates the cyclic components responsible of variability inthe given period of measurement and is equivalent to the total spectralpower. RMSSD and pNN50 estimate high frequency variations in the heartrate and correlate well with the HF component of spectral power.

The NN intervals can also be represented as a geometric pattern, forexample as Poincaré plots, a graphical representation of therelationship between consecutive RR intervals, where an RR interval isplotted against the preceding RR interval. The short term HRV (SD1) andthe long term HRV (SD2) were obtained from the plots. SD1 reflectsmainly respiratory sinus arrhythmia and thus correlates well with the HFcomponent. Another geometric method is sample density distribution ofthe NN intervals. RR triangular index (the integral of the densitydistribution) and the triangular interpolation of NN, TINN (baselinewidth of the distribution measured as a base of a triangle approximatingthe NN interval distribution) were also calculated.

In the frequency domain, Power Spectral Density of the three frequencybands of HRV, namely Very Low Frequency, VLF (0-0.04 Hz), Low Frequency,LF (0.04-0.15 Hz), High Frequency, HF (0.15-0.4 Hz) were calculated. TheHF band is related to respiration and considered to beparasympathetically mediated. LF is influenced both by the sympatheticand parasympathetic components. The LF/HF ratio was also calculated andmay indicate sympathovagal balance. VLF is thought to involvethermoregulatory and peripheral vascular mechanisms. Non-parametricmethods using fast Fourier transforms (FFT) were employed. Total Powerrefers to total power of all frequency bands.

Statistical Analysis: All time and frequency domain HRV parameters weretested for their statistical significance between RBD patients andcontrol subjects. An unpaired student's t-test was used for statisticalanalysis. A p value of ≦0.05 was considered statistically significant.Results:

Patient Selection: Medical record review identified 35 individuals witha clinical diagnosis of RBD. After rescoring and chart review, 24 caseswere excluded based on the exclusion criteria outlined above. Thereasons for exclusion included lack of clinical symptoms i.e.subclinical RBD (4), other neurological and cardiovascular disorders(15), liver transplant (1), diabetes (1), and arrhythmias (3). Theremaining 11 cases were included in the study and consisted of 9 men and2 women (mean age 63.27±7.46 years).

Heart rate variability analysis: HRV as measured by both time domain andspectral measures varied significantly between the control group and thepatients with RBD (see Table 1). Several time domain, frequency domainand geometric measures showed significantly attenuated HRV in the RBDpatients compared to the control group.

TABLE 1 HRV parameters between control and RBD groups RBD patientsControl group p value RR (ms) 936.36 ± 92.77  948.55 ± 179.59 NS SDNN(ms) 18.09 ± 6.39  28.73 ± 11.15 p < 0.01 HR (bpm) 64.75 ± 5.94  65.44 ±11.56 NS SDHR (bpm) 1.84 ± 0.75 2.65 ± 1.04 p < 0.05 RMSSD (ms) 16.98 ±5.89  27.13 ± 12.54 p < 0.03 pNN50 (%) 2.16 ± 2.12  9.71 ± 10.23 p <0.03 SD1 (ms) 12.35 ± 4.75  19.6 ± 9.03 p < 0.03 SD2 (ms) 44.45 ± 20.0768.91 ± 32.04 p < 0.05 RR triangular index 0.04 ± 0.01 0.05 ± 0.02 p <0.04 TINN (ms) 96.36 ± 32.13 150.91 ± 62     p < 0.02 VLF ( 

) 11.09 ± 7.75  22.64 ± 17.72 p < 0.06 LF ( 

)   102 ± 69.57 349.91 ± 294.25 p < 0.01 LF (nu) 61.64 ± 16.43 69.75 ±19.85 NS HF ( 

) 48.91 ± 30.27 133.73 ± 112.2  p < 0.03 HF (nu) 38.36 ± 16.43 30.25 ±19.85 NS Total Power ( 

)   162 ± 98.15 506.27 ± 395.32 p < 0.01 LF/HF 2.15 ± 1.38  3.3 ± 1.97NS Data are presented as mean ± SD. Parameters showing statisticalsignificance are shown in bold

The standard deviation of RR interval, SDNN (p<0.01) and heart rate,SDHR (p<0.05), were lower in RBD than in the control group. RBD patientsalso had significantly lower RMSSD (p<0.03) and pNN50 (p<0.03) than thecontrol subjects (FIG. 2). The RR interval and heart rate were notsignificantly different between the groups.

Standard deviations of the Poincaré plots namely, SD1 (perpendicular tothe line of identity and SD2 (along the line of identity) werecalculated. SD1 describes the short term variability caused mainly byrespiratory sinus arrhythmia. SD2 denotes long term variability. BothSD1 (p<0.03) and SD2 (p<0.05) are lower in RBD compared to the controlgroup. The geometric measures, RR triangular index (p<0.04) and TINN(p<0.01) are also significantly less in the RBD patients compared to thecontrol group (Table 1).

All the spectral power components proved to be lower in patients withRBD vs. the control group. Low Frequency (LF) power (p<0.01), HighFrequency (HF) power (p<0.03) and Total Spectral Power (p<0.01) wereattenuated in RBD patients. However, the normalized units (power in aband divided by the total power-power of VLF) failed to reach asignificant difference between the groups. Although the VLF power andLF/HF ratio also indicated a trend toward a much lower value in the RBDgroup, it was not significantly different between RBD and control groupsas indicated in Table 1. Similar to the time-domain measures, thespectral measures are much lower than the mean for the control group(FIG. 3).

Example 3 Assessment of Heart Rate Variability (HRV) During Wakefulnessin Patients with RBD

Methods: Data from polysomnograms performed between the years 2000 to2008 in 10 RBD patients and 10 age- and sex-matched controls wereretrieved and the pre-sleep segments of EKG channel analyzed for changesin HRV.

Results:

TABLE 2 HRV parameters between control and RBD groups RBD patientsControl group p value RR (ms) 941.5 ± 95.8   945.3 ± 188.98 NS SDNN (ms)17.6 ± 6.49  29.8 ± 11.14 p < 0.01 HR (bpm) 64.437 ± 6.14   65.84 ±12.1  NS SDHR (bpm) 1.784 ± 0.75  2.77 ± 1.01 p < 0.03 RMSSD (ms) 16.21± 5.62  27.27 ± 13.20 p < 0.03 pNN50 (%) 2.03 ± 2.18 10.24 ± 10.61 p <0.03 SD1 (ms) 11.81 ± 4.11  19.73 ± 9.50  p < 0.03 SD2 (ms) 43.89 ±20.93 70.26 ± 33.44 p < 0.05 RR triangular index 0.038 ± 0.01  0.0520.016 p < 0.03 TINN (ms)    92 ± 30.43   157 ± 61.78 p < 0.01 VLF ( 

) 11.2 ± 8.12  24.6 ± 17.37 p < 0.04 LF ( 

) 104.3 ± 72.56  382.1 ± 289.02 p < 0.01 LF (nu) 62.97 ± 16.66 74.91 ±10.62 p < 0.08 HF ( 

)  45.3 ± 29.40  134.6 ± 118.22 p < 0.03 HF (nu) 37.03 ± 16.66 25.09 ±10.62 p < 0.08 Total Power ( 

)  160.8 ± 102.85  541.3 ± 398.30 p < 0.01 LF/HF 2.26 ± 1.39 3.60 ± 1.77p < 0.08 Data are presented as mean ± SD. Parameters showing statisticalsignificance, shown in bold

A wide variety of HRV measures, including standard deviation of N-Nintervals (SDNN) and heart rate (SDHR), root mean square difference ofsuccessive RR intervals (RMSSD) percentage of number of pairs ofadjacent RR intervals differing by more than 50 ms (pNNSO), short termHRV (SD1) and long term HRV (SD2) obtained from the Poincaré plot, RRtriangular index, triangular interpolation of NN (TINN), spectral powersin the Very Low Frequency (VLF), Low Frequency (LF) and High Frequency(HF) bands as well as Total Spectral Power, were significantly lower inRBD patients than controls (Table 2). The LF/HF ratio, normalized LF (LFnu) and HF (HF nu) also showed a trend in the same direction.

Example 4 EKG can be Used to Identify Prodromal Parkinson's Diseaseand/or Parkinson's-Like Disease

A person experiencing symptoms of RBD such as loss of normal voluntarymuscle atonia during REM sleep, associated with complex behavior whiledreaming visits the doctor's office and is advised to undergo at leastabout a 5-minute EKG. The EKG measures the person's HRV. The algorithmof the present invention is applied to the person's EKG results toassess his HRV and the associated variables, and then compares theperson's HRV to the standard HRV range which is indicative ofParkinson's disease or Parkinson's-like disease. The person's EKGresults fall into the EKG range predetermined to be indicative ofParkinson's disease or Parkinson's-like disease, suggesting that thisperson may have prodromal/pre-motor Parkinson's disease orParkinson's-like disease. But the person does not experience any motorsymptoms on the USPRDS and HY scales at this stage.

The person subsequently undergoes a genetic testing for Parkinson'sdisease. The person is screened for a mutation in the following genes:leucine-rich repeat kinase 2 (LRRK2), α-synuclein (SNCA), parkin (PRKN),ubiquitin C-terminal hydrolase L1 (UCH-L1), oncogene DJ-1 gene,PTEN-induced protein kinase 1 (PINK1), and microtubule-associatedprotein tau (MAPT). The mutations include substitution, deletion,insertion, duplication, triplication or a combination thereof. Theperson further undergoes brain imaging. He takes both PET scan and MRI.The genetic screening results indicate that this person has mutationsthe LRRK2 gene, and the brain imaging results also suggest that thisperson lowered activity in certain brain regions. Thus, the method ofthe present invention can be used to diagnose premotor or prodromalParkinson's disease or Parkinson's-related disease, at an early stage,prior to the onset of diagnosable motor symptoms.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of detecting an increased risk ofdeveloping Parkinson's disease or Parkinson's-like disease indicated bya loss of standard deviation of heart rate (SDHR), said methodcomprising: a) selecting a subject that does not exhibit motor symptomsindicative of Parkinson's disease or Parkinson's-like disease; b)obtaining 5 or fewer minutes of heart rate data; c) determining a SDHRof said subject from the heart rate data; d) detecting the increasedrisk for developing Parkinson's disease or Parkinson's-like disease ifsaid SDHR of said subject is less than a control SDHR; and e) taking asample for genetic testing, if the increased risk for developingParkinson's disease or Parkinson's-like disease has been detected insaid subject in step d).
 2. The method of claim 1, wherein the subjectis in a wakeful state or awake while measuring heart rate.
 3. The methodof claim 1, further comprising treating said subject.
 4. The method ofclaim 1, wherein the subject scores a 0 on a scale selected from aUnified Parkinson's Disease Rating Scale (UPDRS) and a Hoehn and Yahrscale.
 5. The method of claim 1, wherein the control SDHR is obtainedfrom one or more healthy subjects.
 6. The method of claim 1, wherein thecontrol SDHR is obtained from one or more subjects selected from asubject that is not diagnosed with Parkinson's disease orParkinson's-like disease.
 7. The method of claim 1, wherein the subjectdoes not exhibit motor symptoms indicative of Parkinson's Disease orParkinson's like disease as assessed by a scale selected from the Hoehnand Yahr Scale and the Unified Parkinson's Disease Rating Scale (UPDRS).8. The method of claim 1, wherein the SDHR of said subject is below theaverage for the control SDHR.
 9. A method of detecting an increased riskof developing Parkinson's disease or Parkinson's-like indicated by aloss of standard deviation of heart rate (SDHR), said method comprising:a) selecting a subject that does not exhibit motor symptoms indicativeof Parkinson's disease or Parkinson's-like disease as assessed by theHoehn and Yahr Scale or the Unified Parkinson's Disease Rating Scale(UPDRS); b) obtaining 5 or fewer minutes of heart rate data from saidsubject; c) determining a SDHR of said subject from the heart rate data;d) detecting the increased risk for developing Parkinson's disease orParkinson's-like disease if said SDHR of said subject is less than acontrol SDHR, and e) taking a sample for genetic testing, if theincreased risk for developing Parkinson's disease or Parkinson's-likedisease has been detected in said subject in step d).